The ACEP Level A recommendation regarding the use of tPA in patients with acute ischemic stroke states that "IV tPA should be offered to acute ischemic stroke patients who meet NINDS inclusion/exclusion criteria and can be treated within 3 hours after symptom onset."

Overall, I think making a Level A recommendation based on the NINDS study is fraught with issues. Although other research was considered in this recommendation, NINDS was the only randomized, controlled trial (RCT) that played into the recommendation. Making such a strong recommendation based on a single RCT is problematic. Typically, Level A is accorded to recommendations with multiple studies backing it up.

NINDS has never been replicated. So what we are stuck with is a recommendation based on 333 patients studied in 1995. NINDS itself had two parts. In part 1,291 patients were investigated with a primary outcome of improvement in National Institute of Health Stroke Scale (NIHSS) at 24 hours, and there was no difference found in the primary outcome. In the second part, 333 patients were studied with a different primary endpoint of improvement at 90 days, and a number needed to treat (NNT) of 8 was found, along with a number needed to harm of 16 (6.4% intracranial hemorrhage rate).

However, the results were biased. Those that got tPA were less sick at baseline than the placebo group and were thus more likely to be more functional at 90 days. Additionally, an equal number of patients were enrolled in the 0-90 minute group as in the 90-180 minute group. This causes the study to lack external validity as this is not what we see in clinical practice where the majority of patients present in the 90-180 minute time window.

Additionally, the NINDS group appears to have changed their primary endpoint halfway through the study when they found no benefit in the initial primary outcome. This is a research faux pas that we would never let slide today without intense scrutiny.

In a debate at the EMCrit Critical Care Conference, Andy Jagoda brought up a point that I think is important here. When ACEP put this committee together, they made an error in not putting any people on the committee who were tPA skeptics. As a result, it's difficult for the EM [emergency medicine] community to accept these clinical guidelines, since greater than 50% of EM physicians are unconvinced of the benefit of the drug. Hopefully, the reopening of the discussion will allow these voices to be heard.

What are your thoughts about how these guidelines have or have not changed clinical practice in the emergency department with regard to acute ischemic stroke?

This question is more difficult to answer. I work at an academic center that is also a stroke center. We have a policy on the use of tPA in suspected CVA, and this guideline changes nothing for my clinical practice. However, most physicians do not work in places like mine. These docs are on the front lines and often have to make decisions without the same level of consultation services or support that I have. I imagine that a policy endorsed by our dominant national organization affects the way they function.

For all of my criticism, I do think that the recommendations were smartly worded. The Level A recommendation states that tPA should be offered to all patients who qualify in the less-than-3-hour time window. It doesn't say that they should all get the drug. This opens the decision to clinical gestalt, physician expertise, and discussion with the patient.

However, this is still the strongest endorsement a U.S. national EM organization has given and, as such, I think a physician who decides (with the patient or surrogate) not to give the drug should provide ample explanation of their decision, to protect themselves.

Lessons to learn?

In the absence of conclusive evidence, which many of us believe we don't have, this debate will continue to rage on. I encourage everyone to read the literature for themselves, listen to smart people discuss it (Jerry Hoffman, David Newman, Michelle Johnston etc.) and decide for yourselves. Ultimately, your patient will ask "what would you do?" and it'll be up to us to give them the best information available to aid in their decision.

Finally, let the history of tPA in acute ischemic stroke be a warning for us to heed in the future. If the FDA, AHA, and other professional organizations had called for a replication of NINDS in a larger group to validate the results, we would likely not be having this debate today.

A single small study should not be practice-changing. Our patients deserve more than that. This caution is extremely important as novel therapies emerge for treatment of stroke and other diseases. Last year, three studies (1, 2, 3) were published in the New England Journal of Medicine regarding endovascular retrieval devices in ischemic stroke. All three were negative studies. When a positive study emerges, we shouldn't rush to adopt the treatment. We should demand replication.

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